IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma

Satoshi Kofuji; Akiyoshi Hirayama; Alexander Otto Eberhardt; Risa Kawaguchi; Yuki Sugiura; Oltea Sampetrean; Yoshiki Ikeda; Mikako Warren; Naoya Sakamoto; Shuji Kitahara; Hirofumi Yoshino; Daisuke Yamashita; Kazutaka Sumita; Kara Wolfe; Lisa Lange; Satsuki Ikeda; Hiroko Shimada; Noriaki Minami; Akshiv Malhotra; Shin Morioka; Yuki Ban; Maya Asano; Victoria L. Flanary; Annmarie Ramkissoon; Lionel M.L. Chow; Juri Kiyokawa; Tomoyuki Mashimo; Greg Lucey; Sergey Mareninov; Tatsuya Ozawa; Nobuyuki Onishi; Koichi Okumura; Jumpei Terakawa; Takiko Daikoku; Trisha Wise-Draper; Nazanin Majd; Kaori Kofuji; Mika Sasaki; Masaru Mori; Yonehiro Kanemura; Eric P. Smith; Dimitrios Anastasiou; Hiroaki Wakimoto; Eric C. Holland; William H. Yong; Craig Horbinski; Ichiro Nakano; Ralph J. DeBerardinis; Robert M. Bachoo; Paul S. Mischel; Wataru Yasui; Makoto Suematsu; Hideyuki Saya; Tomoyoshi Soga; Ingrid Grummt; Holger Bierhoff; Atsuo T. Sasaki

doi:10.1038/s41556-019-0363-9

IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma

Satoshi Kofuji, Akiyoshi Hirayama, Alexander Otto Eberhardt, Risa Kawaguchi, Yuki Sugiura, Oltea Sampetrean, Yoshiki Ikeda, Mikako Warren, Naoya Sakamoto, Shuji Kitahara, Hirofumi Yoshino, Daisuke Yamashita, Kazutaka Sumita, Kara Wolfe, Lisa Lange, Satsuki Ikeda, Hiroko Shimada, Noriaki Minami, Akshiv Malhotra, Shin MoriokaYuki Ban, Maya Asano, Victoria L. Flanary, Annmarie Ramkissoon, Lionel M.L. Chow, Juri Kiyokawa, Tomoyuki Mashimo, Greg Lucey, Sergey Mareninov, Tatsuya Ozawa, Nobuyuki Onishi, Koichi Okumura, Jumpei Terakawa, Takiko Daikoku, Trisha Wise-Draper, Nazanin Majd, Kaori Kofuji, Mika Sasaki, Masaru Mori, Yonehiro Kanemura, Eric P. Smith, Dimitrios Anastasiou, Hiroaki Wakimoto, Eric C. Holland, William H. Yong, Craig Horbinski, Ichiro Nakano, Ralph J. DeBerardinis, Robert M. Bachoo, Paul S. Mischel, Wataru Yasui, Makoto Suematsu, Hideyuki Saya, Tomoyoshi Soga, Ingrid Grummt, Holger Bierhoff, Atsuo T. Sasaki

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Abstract

In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.

Original language	English (US)
Pages (from-to)	1003-1014
Number of pages	12
Journal	Nature cell biology
Volume	21
Issue number	8
DOIs	https://doi.org/10.1038/s41556-019-0363-9
State	Published - Aug 1 2019

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Cell Biology

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Kofuji, S., Hirayama, A., Eberhardt, A. O., Kawaguchi, R., Sugiura, Y., Sampetrean, O., Ikeda, Y., Warren, M., Sakamoto, N., Kitahara, S., Yoshino, H., Yamashita, D., Sumita, K., Wolfe, K., Lange, L., Ikeda, S., Shimada, H., Minami, N., Malhotra, A., ... Sasaki, A. T. (2019). IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma. Nature cell biology, 21(8), 1003-1014. https://doi.org/10.1038/s41556-019-0363-9

Kofuji, S, Hirayama, A, Eberhardt, AO, Kawaguchi, R, Sugiura, Y, Sampetrean, O, Ikeda, Y, Warren, M, Sakamoto, N, Kitahara, S, Yoshino, H, Yamashita, D, Sumita, K, Wolfe, K, Lange, L, Ikeda, S, Shimada, H, Minami, N, Malhotra, A, Morioka, S, Ban, Y, Asano, M, Flanary, VL, Ramkissoon, A, Chow, LML, Kiyokawa, J, Mashimo, T, Lucey, G, Mareninov, S, Ozawa, T, Onishi, N, Okumura, K, Terakawa, J, Daikoku, T, Wise-Draper, T, Majd, N, Kofuji, K, Sasaki, M, Mori, M, Kanemura, Y, Smith, EP, Anastasiou, D, Wakimoto, H, Holland, EC, Yong, WH, Horbinski, C, Nakano, I, DeBerardinis, RJ , Bachoo, RM, Mischel, PS, Yasui, W, Suematsu, M, Saya, H, Soga, T, Grummt, I, Bierhoff, H & Sasaki, AT 2019, 'IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma', Nature cell biology, vol. 21, no. 8, pp. 1003-1014. https://doi.org/10.1038/s41556-019-0363-9

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title = "IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma",

abstract = "In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.",

author = "Satoshi Kofuji and Akiyoshi Hirayama and Eberhardt, {Alexander Otto} and Risa Kawaguchi and Yuki Sugiura and Oltea Sampetrean and Yoshiki Ikeda and Mikako Warren and Naoya Sakamoto and Shuji Kitahara and Hirofumi Yoshino and Daisuke Yamashita and Kazutaka Sumita and Kara Wolfe and Lisa Lange and Satsuki Ikeda and Hiroko Shimada and Noriaki Minami and Akshiv Malhotra and Shin Morioka and Yuki Ban and Maya Asano and Flanary, {Victoria L.} and Annmarie Ramkissoon and Chow, {Lionel M.L.} and Juri Kiyokawa and Tomoyuki Mashimo and Greg Lucey and Sergey Mareninov and Tatsuya Ozawa and Nobuyuki Onishi and Koichi Okumura and Jumpei Terakawa and Takiko Daikoku and Trisha Wise-Draper and Nazanin Majd and Kaori Kofuji and Mika Sasaki and Masaru Mori and Yonehiro Kanemura and Smith, {Eric P.} and Dimitrios Anastasiou and Hiroaki Wakimoto and Holland, {Eric C.} and Yong, {William H.} and Craig Horbinski and Ichiro Nakano and DeBerardinis, {Ralph J.} and Bachoo, {Robert M.} and Mischel, {Paul S.} and Wataru Yasui and Makoto Suematsu and Hideyuki Saya and Tomoyoshi Soga and Ingrid Grummt and Holger Bierhoff and Sasaki, {Atsuo T.}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2019",

month = aug,

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doi = "10.1038/s41556-019-0363-9",

language = "English (US)",

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T1 - IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma

AU - Kofuji, Satoshi

AU - Hirayama, Akiyoshi

AU - Eberhardt, Alexander Otto

AU - Kawaguchi, Risa

AU - Sugiura, Yuki

AU - Sampetrean, Oltea

AU - Ikeda, Yoshiki

AU - Warren, Mikako

AU - Sakamoto, Naoya

AU - Kitahara, Shuji

AU - Yoshino, Hirofumi

AU - Yamashita, Daisuke

AU - Sumita, Kazutaka

AU - Wolfe, Kara

AU - Lange, Lisa

AU - Ikeda, Satsuki

AU - Shimada, Hiroko

AU - Minami, Noriaki

AU - Malhotra, Akshiv

AU - Morioka, Shin

AU - Ban, Yuki

AU - Asano, Maya

AU - Flanary, Victoria L.

AU - Ramkissoon, Annmarie

AU - Chow, Lionel M.L.

AU - Kiyokawa, Juri

AU - Mashimo, Tomoyuki

AU - Lucey, Greg

AU - Mareninov, Sergey

AU - Ozawa, Tatsuya

AU - Onishi, Nobuyuki

AU - Okumura, Koichi

AU - Terakawa, Jumpei

AU - Daikoku, Takiko

AU - Wise-Draper, Trisha

AU - Majd, Nazanin

AU - Kofuji, Kaori

AU - Sasaki, Mika

AU - Mori, Masaru

AU - Kanemura, Yonehiro

AU - Smith, Eric P.

AU - Anastasiou, Dimitrios

AU - Wakimoto, Hiroaki

AU - Holland, Eric C.

AU - Yong, William H.

AU - Horbinski, Craig

AU - Nakano, Ichiro

AU - DeBerardinis, Ralph J.

AU - Bachoo, Robert M.

AU - Mischel, Paul S.

AU - Yasui, Wataru

AU - Suematsu, Makoto

AU - Saya, Hideyuki

AU - Soga, Tomoyoshi

AU - Grummt, Ingrid

AU - Bierhoff, Holger

AU - Sasaki, Atsuo T.

PY - 2019/8/1

Y1 - 2019/8/1

N2 - In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.

AB - In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.

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JO - Nature cell biology

JF - Nature cell biology

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IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma

Abstract

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